The quest for a prophylactic AIDS vaccine is ongoing and it is probable that the successful vaccine must elicit protective antibody responses. Regardless of the mechanism of antibody-mediated protection, antibody persistence and appropriate T cell help are emerging as significant problems in AIDS vaccine development. The problem of antibody persistence is seen clearly in the RV144 trial. Protection was as highest in the first year but waned rapidly to background in parallel with anti-V2 antibodies that were associated with reduced risk of infection. Poor antibody persistence is not unique to RV144. It occurred in the VAX003/VAX004 efficacy trials, also using gp120 immunogens, and it has been observed repeatedly in gp120 vaccine trials in humans and non-human primates. Poor antibody persistence to gp120 is entwined with a second major problem. How to elicit necessary CD4+ T cell help without establishing fertile fields for increased HIV replication at sites of exposure, blunting protection, or increasing acquisition. It appears that vaccine-elicited CD4+ T cell and innate immune responses are associated with increased acquisition in the Step/Phambili trials that used an Ad5Hu- HIV T-cell vaccine as the immunogen. There are reports of vaccine-associated increased acquisition in non- human primate (NHP) models using other vectors and immunogens in addition to AdHu5. Taken together, the conjoint problems of antibody persistence and T cell balance must be solved for any antibody-based HIV vaccine to be effective. This requirement introduces a new concept for HIV vaccine development based on achieving balanced T cell and humoral responses, contrasting sharply with current approaches that focus on one arm or the other, or that seek to maximize both arms in parallel. Exploration of this concept forms the foundation of the proposed program that will test the central hypothesis that an HIV vaccine candidate can elicit durable antibody responses supported by a balanced CD4+ T cell profile that favors protection. This hypothesis is based on published work from the investigators and on solid preliminary data in RM models. This hypothesis will be tested via three highly interactive projects. Dr. Robert C. Gallo (IHV) will lead the program. Dr. Anthony L. DeVico (IHV) will lead Project 1 that exploits DNA/Protein co-immunization protocols to test hypotheses regarding the disposition of plasma cell subsets and how they determine the unusually poor durability of anti-gp120 antibody responses. Dr. George K. Lewis (IHV) will lead Project 2 to determine how vaccine elicited CD4+ T cells attenuate antibody-mediated protection. Dr. Guido Silvestri (Emory) will lead Project 3 to determine the phenotypes of vaccine-elicited CD4+ T cells and innate immune signatures that favor durable protection. In terms of major outcomes, this work is expected to fully identify the mechanism of poor anti-Env antibody persistence and to overcome this problem while maintaining safe levels of CD4+ T cells that don't blunt protection. These results are expected to fundamentally advance AIDS vaccine development for which broad durable protection is the Holy Grail.